Cytokine regulation of intestinal epithelial restitution

肠上皮恢复的细胞因子调节

• 批准号: 10372401
• 负责人: D Brent Polk
• 金额: $ 34.77万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-16 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10372401
• 关键词: Cytokine; regulation; intestinal; epithelial; restitution

PROJECT SUMMARY Inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis, is a chronic inflammatory disorder of the gastrointestinal tract. IBD afflicts nearly 1.5 million people in the United States. The exact causes of IBD are unknown, but they are thought to generally involve dysregulated host immune responses to commensal microorganisms in genetically susceptible individuals. Tumor necrosis factor (TNF), a major immune cytokine, has a central role in the disease process. While anti-TNF therapies are a part of the medical regimen for many IBD patients, there is mounting evidence that the complete blockade of TNF signaling is not appropriate in the long-term for many. For example, most patients treated with anti-TNF biologics stop responding to the therapy within 5 years. We and others have demonstrated that TNF signaling through its lesser-characterized receptor TNFR2 has many beneficial functions on the repair of the colonic epithelial barrier, a crucial mitigating aspect of IBD, and on the regulation of immune cells including cytotoxic (CD8+) T lymphocytes and regulatory T cells. This application will follow-up on these novel observations to explore the mechanisms that underlie TNFR2's protective effects on CD8+ T cells and colonic epithelial stem cell populations in the setting of colonic injury and inflammation. Specifically, we will: 1) determine the mechanisms by which TNFR2 regulates the pathogenicity of CD8+ T cells in colitis, 2) elucidate the role of TNFR2 in regulation of CD8+ T cell subpopulations and their colonic localization, and 3) define the role of epithelial TNFR2 on colonic epithelial stem cell dynamics and mucosal healing. These studies will reveal important cellular and molecular patterns that may underlie the pathophysiology of IBD.

项目概要 炎症性肠病 (IBD)，包括克罗恩病和溃疡性结肠炎，是一种慢性疾病 胃肠道炎症性疾病。在美国，IBD 困扰着近 150 万人。 IBD 的确切原因尚不清楚，但一般认为与宿主免疫失调有关 遗传易感个体对共生微生物的反应。肿瘤坏死因子（TNF） 主要的免疫细胞因子，在疾病过程中具有核心作用。虽然抗 TNF 疗法是治疗的一部分 对于许多 IBD 患者的治疗方案，越来越多的证据表明，完全阻断 TNF 从长远来看，信号传递对许多人来说并不合适。例如，大多数接受抗 TNF 治疗的患者 生物制剂在 5 年内不再对治疗产生反应。我们和其他人已经证明 TNF 信号传导 通过其特征较少的受体 TNFR2 对结肠修复具有许多有益的功能 上皮屏障（IBD 的一个重要缓解方面）以及免疫细胞（包括细胞毒性）的调节 (CD8+) T 淋巴细胞和调节性 T 细胞。该应用程序将跟踪这些新颖的观察结果 探索 TNFR2 对 CD8+ T 细胞和结肠上皮干细胞保护作用的机制 结肠损伤和炎症环境中的细胞群。具体来说，我们将： 1）确定 TNFR2 调节结肠炎中 CD8+ T 细胞致病性的机制，2) 阐明 TNFR2 在调节 CD8+ T 细胞亚群及其结肠定位中的作用，以及 3) 定义了 上皮TNFR2对结肠上皮干细胞动力学和粘膜愈合的影响。这些研究将揭示 可能是 IBD 病理生理学基础的重要细胞和分子模式。